Cancer cells express cancer cell-specific antigen resulting from the inductions of over-expression and mutation for specific proteins, which are removed due to the auto immune reaction of patient (Nagorsen D. et al., Clin. Cancer Res. 9, pp 4296-4303, 2003; Yee C et al., J. Exp. Med. 192, pp 1637-1644, 2000; Castelli C et al., J. Cell Physiol., 182, pp 323-331, 2000). Those immune reactions against cancer cells are represented by antigen-presenting cell (APC) such as dendritic cell which is the same with normal immune reaction and the cancer cells are removed by activation of appropriate T cell and B cell with APC (Jay A. et al., J. Clin. Invest. 113, pp 1515-1525, 2004).
Cancer cells cause anergy or tolerance through various mechanisms for examples, the decrease of MHC molecules, inhibition of co-stimulatory molecule expression, induction of immunosuppressive substance such as TGF-β and IL-10, infiltration of CD4+CD25+ regulatory T cell in cancer tissues etc, and try to protecting from the anti-cancer immune reaction (Smyth M J et al., Nat. Immunol. 2, pp 293-299, 2001; Dunn G P et al., Immunity 21, pp 137-148, 2004). The anti-cancer immune reactions depend on cell-mediated immunity. In particular, CD8+ T cells (CTLs) are critical to remove cancers, and keep the immunologic memory (Maeurer M J et al., Int. Rev. Immunol. 14, pp 97-132, 1997).
There need two kinds of signals to induce T cell activation (Mondino A et al., J. Leukoc. Biol. 55, pp 805-815, 1994), i.e., first signal, namely antigen specific signal, is carried out by TCR and the second signal is carried out by co-stimulatory molecules. Ig (immunoglobulin) family and TNFR family are well known as co-stimulatory molecules. Since the immune agonistic and antagonistic roles of those molecules were publicly known, various treatment methods using thereby have been tried till now. At present, there have been reported that 4-1BB (CD137), CTLA-4, CD28, LIGHT, PD-1, CD27 etc showed potent anti-cancer activity among them (Ye Z et al., Nat. Med. 8, pp 343-348, 2002; Phan G Q et al., Proc. Natl. Acad. Sci. USA, 100, pp 8372-8377, 2003; Li Q et al., J. Immunother., 25, pp 304-313, 2002; Yu Pet al., Nat. Immunol. 5, pp 141-149, 2004; Iwai Y et al., Int. Immunol. 17, pp 133-144, 2005; Arens R et al., J. Exp. Med. 199, pp 1595-1605, 2004).
There have been reported that 4-1BB induces the expression of CTL and IFN-γ, and agonistic anti-4-1BB mAb on cancer treatment have been tried by many researchers (Shuford W W. et al, J. Exp. Med. 186, pp 47-55, 1997).
CTLA-4 has been reported to limit the immune reaction and the inhibition of CTLA-4 signal transfer expressed by activated T cells prevents the proliferation of cancer cell due to maximized activation of T cell (Phan G Q et al., Proc. Natl. Acad. Sci. USA. 100, pp 8372-8377, 2003).
The present inventors have been tried to discover the function of anti-4-1BB antibody and finally found that the treatment using by agonistic anti-4-1BB antibody and antagonistic anti-CTLA-4 antibody increases cancer cell-specific CD8+ T cell, which induces the production of CD8+ T cell expressing CD11c molecule resulting in infiltrating into the tumor differently from other co-stimulatory molecules. The inhibition of cancer cell proliferation through the administration of agonistic anti-4-1BB antibody is caused by the abundant infiltration of CD11c+CD8+ T cells in tumor and highly expressed IFN-γ.
Accordingly, the present invention has been completed by confirming that the treating effect of humanized anti-4-1BB antibody and/or antagonistic anti-CTLA-4 antibody on cancer is caused by increased CD11c+CD8+ T cell resulting in potent inhibiting effect on cancer by the intensification of CTL function and IFN-γ expression and further the effect is reinforced by the inhibition of CTLA-4 signal transfer.
These and other objects of the present invention will become apparent from the detailed disclosure of the present invention provided hereinafter.